The Appeal of the CRISPR Decision

April 18, 2017

On Friday, CRISPR Therapeutics, a leading gene-editing company headquartered in Cambridge, Massachusetts and the Regents of the University of California and their partners, co-owners of patent technology relating to CRISPR-Cas9 genome editing technology, announced that they have appealed to the U.S. Court of Appeals for the Federal Circuit the decision by the United States Patent Trial and Appeal Board (“PTAB”) that there was no interference-in-fact between the claims in interference between CRISPR Therapeutics and the University of California and the Broad Institute, Harvard University and the Massachusetts Institute of Technology.[1]

On February 15, 2017 the PTAB ruled that The Broad patents with claims covering the application of CRISPR-Cas9 in eukaryotic cells was distinct from the invention claimed by CRISPR Therapeutics and the University of California.[2] In that decision, the PTAB concluded that although the claims overlap, the scope of the respective parties’ claim sets as presented did not define the same patentable invention. The PTAB terminated the interference action without deciding which party first invented the use of the CRISPR-Cas9 technology in eukaryotic cells. CRISPR Therapeutics and the University of California are now asking the Federal Circuit Court of Appeals to review and reverse the PTAB’s decision.

In parallel with the appeal, CRISPR Therapeutics and the University of California are pursuing applications with the United States Patent Office and worldwide to obtain patents claiming the CRISPR-Cas9 technology and its use in non-cellular and cellular settings, including eukaryotic cells. Corresponding patents have already been granted in the United Kingdom and the European Patent Office will also reportedly grant a patent which will issue on May 10, 2017. The earliest patent application describing the CRISPR-Cas9 genome editing technology and its use was filed by CRISPR Therapeutics and the University of California on May 25, 2012, while The Broad’s earliest patent application was filed more than six months later, on December 12, 2012.

The Genesis of the CRISPR Gene Editing Technology

CRISPR has been called the greatest biotech invention of all time. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. The CRISPR-Cas9 technique is derived from a naturally occurring defense mechanism developed by bacteria over millions of years to defend themselves from viral infections. As viruses attempt to invade the bacteria, the bacteria launch RNAs that attack a recognized virus. After the virus is repelled, what remains in the bacterial DNA are short sequence repetitions or “palindromes” which become built-up over time. CRISPR are segments of prokaryotic DNA containing short, repetitive base sequences. In a palindromic repeat, the sequence of nucleotide is the same in both directions. Each repetition is followed by short segments of spacer DNA from previous exposures to foreign DNA (from a virus or plasmid). Small clusters of cas (CRISPR-associated system) genes are located next to CRISPR sequences.

CRISPR-Cas genome editing techniques have many potential applications – from potential cures for cancer in medicine to the creation of super crops in agriculture. The use of CRISPR-Cas9-gRNA complex for genome editing was the American Association for the Advancement of Science’s choice for breakthrough of the year in 2015. It all began in 2012, when University of California biochemist, Jennifer Doudna, and others published a scientific paper on CRISPR titled: “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity”. In this paper, Doudna showed that the gene-editing technology could be used to cut DNA in a test tube at targeted sitesThese advances spawned efforts to edit genomes with the modified CRISPR-Cas9 system. Later, Doudna filed a patent application for CRISPR.

Actually, the first description of what would later be called CRISPR came from an Osaka University researcher, Yoshizumi Ishino, who in 1987 accidentally cloned part of a CRISPR together with the iap gene. The organization of the repeats was unusual because repeated sequences are typically arranged consecutively along DNA. However, the function of the interrupted clustered repeats was not known or appreciated at the time.

Then in 2013, in another scientific journal, MIT bioengineer, Feng Zhang, and his team of researchers reported developing a CRISPR system that could edit genomes in the living cells of mice and humans.[3] When Zhang filed his own patent application, he requested that the United States Patent Office “fast track” its patent review process. So, the University of California, which was waiting for a decision from the patent office on its own patent application, filed an interference proceeding to determine who was the first to invent the gene-editing tool CRISPR-Cas9 arguing that The Broad’s technique overlapped with its CRISPR technique.[4] The result was that although the University of California filed first, the PTAB actually awarded the patent to The Broad and MIT in April 2014.

Editing Eukaryotic Cells

Editing of eukaryotic cells is what researchers led by The Broad’s scientists did. The University of California researchers never demonstrated such editing in eukaryotic cells. The USPTO ruled: “It is undisputed that [Doudna’s 2012 paper] does not report the results of experiments using the CRISPR-Cas9 system in a eukaryotic cell.”

The Claim

When it filed for patents based on the 2012 discovery by Doudna and her chief collaborator, Emmanuelle Charpentier, the University of California reached for the moon, asking for patents covering CRISPR genome editing in any setting, including eukaryotic cells and other cell types.” Eukaryotic cells are those with a nucleus, like animal and plant cells — including, of course, human cells. But the 2012 experiments showed only that CRISPR could cut DNA that’s floating in a test tube.

Did the Patents Overlap?

In its interference claim, the University of California argued that the patents overlapped, because without its pioneering work on CRISPR, The Broad’s work could never have taken place. The Broad argued that its patents on the use of CRISPR to edit animal and human cells didn’t overlap with the University of California’s patent applications because use of the gene editing technique had not been proven by Doudna and her research team in eukaryotic cells.

Obviousness or Innovation?

What they argued about is not just who invented CRISPR first, but also who first unveiled key aspects of the gene editing technology. The University of California claimed that after the publication of Doudna’s 2012 CRISPR paper, anyone could have applied the technique to edit eukaryotic cells — the cells of animals and people. They argued it was an “obvious” development of the technology, so Zhang’s patents were without merit.[5] For its part, The Broad argued Zhang’s demonstration of the technique in eukaryotic cells was a monumental inventive leap and since Doudna was unable to demonstrate the technique on eukaryotic cells Zhang’s group deserved the patents.

A Reasonable Expectation of Success?

The University of California countered with the fact that six other research groups were working on using CRISPR in eukaryotic cells six months after Doudna’s 2012 paper was published, and they were using the same system Doudna used. Its attorneys argued: “There was no special sauce here” and that Zhang and his team had “a reasonable expectation of success” using “conventional methods” — meaning that Zhang had not accomplished anything particularly inventive to successfully use CRISPR in animal and human cells.[6] The Broad argued that even though other groups were trying to use the CRISPR system in eukaryotic cells, no one before Zhang was able to make the system work. So there was hope of success, but that this was a far cry from a reasonable expectation of success. The Broad argued: “There was no reasonable expectation of success before 2012,” and “There was no reasonable expectation after 2012.”

However, as the PTAB observed: “Regardless of how many groups achieved success in eukaryotic cells, we are not persuaded that such success indicates there was an expectation of success before the results from these experiments were known. The unpublished results of research groups are not necessarily an indication of whether ordinarily skilled artisans would have expected the results achieved. Instead of viewing such work as evidence of an expectation of success, we consider the number of groups who attempted to use CRISPR-Cas9 in eukaryotic cells to be evidence of the motivation to do so, an issue that is not in dispute.”[7]

In reaching its decision that there was no interference, the PTAB also extensively cited Doudna’s own contemporaneous statements that “conflict with testimony prepared for litigation”, to the press and others, in concluding there was no overlapping.  The PTAB cited a written statement made by Doudna where she said: “it was not known whether such a bacterial system would function in eukaryotic cells.”[8] She further stated that her team had experienced “many frustrations” getting CRISPR to work in human cells. Genetic “techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics,” Doudna said. [9]

Dana Carroll, a biochemist at the University of Utah in Salt Lake City who specializes in ways to cut DNA, testified on behalf of the University of California arguing that applying the discovery to human cells was “obvious”. However, in concluding that there was no reasonable likelihood that the technique would function with eukaryotic cell lines and that the application of the technique was not obvious, the PTAB held: “After considering all of the evidence, we are persuaded that Dr. Carroll did not express an expectation that the CRISPR-Cas9 system could be used successfully in eukaryotic cells. Although we agree that Dr. Carroll expressed a suggestion and an expectation that the necessary experiments would be done, he did not state any expectation of what the results would be. Instead, Dr. Carroll pointed to differences between CRISPR-Cas9 and systems that work in eukaryotic cells (ZFNs and TALENs) and wrote: “There is no guarantee that Cas9 will work effectively on a chromatin target or that the required DNA-RNA hybrid can be stabilized in that context.” (citations omitted) We fail to see how “no guarantee” indicates an expectation of success. Although there need not be absolute predictability for a conclusion of obviousness (see In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985), at best, Dr. Carroll’s statement highlights some specific reasons why the CRISPR-Cas9 system might fail in eukaryotes. Thus, the only conclusion we draw from Dr. Carroll’s statement is that at the time, he did not have a reasonable expectation that the system would work.[10]

Why Is This Important?

Determining who owns the intellectual property of the CRISPR-Cas9 technology basically means determining who will become rich. The CRISPR-Cas9 gene editing technology has potential applications in everything from medicine to agriculture. A patent holder can impose hefty licensing fees. While the two scientists involved in the patent dispute have said they intend to release all intellectual property rights to researchers for free, licensing fees could still be charged to private companies wanting to use the technology and willing to invest millions of dollars in CRISPR research. Already the technology has been licensed to various companies to develop everything from genetically engineered mice to CRISPR reagent kits.

So What Happens Now?

It would appear that the appeal to the Federal Circuit Court of Appeals could put the brakes on efforts to license the gene editing technology and throw the future ownership of the CRISPR-Cas9 technology into question. The patent The Broad received is for the use of CRISPR genome-editing technology in eukaryotic cells. The patents that the University of California filed for in 2012 but which had been held up by the legal proceeding are for all cells.

The PTAB decision states that: “[i]t is well-settled that a narrow species can be non-obvious and patent eligible despite a patent on its genus” Abbvie Inc. v. Mathilda & Terence Kennedy Inst. of Rheumatology Trust, 764 F.3d 9 1366, 1379 (Fed. Cir. 2014) and that “earlier disclosure of a genus does not necessarily prevent patenting a species member of the genus.” Eli Lilly & Co. v. Bd. of Regents of Univ. of Wash., 334 F.3d 1264, 1270 (Fed.Cir. 2003).[11] Thus, the decision suggests that a larger category of something can be patented separately from a subset of it. The PTAB’s decision that there was no “interference in fact” means that the CRISPR patents issued to The Broad covered different inventions than those in the patents applied for by CRISPR Technologies and the University of California and its partners. Crucially, the PTAB held that it was not “obvious” how to go from Doudna’s work to Zhang’s eukaryotic cell innovation.

The appeal of the PTAB decision to the Federal Circuit would seem to indicate that the parties – who have reportedly invested more than 15 million dollars in litigating the case to date – are not close to an agreement to jointly license the technology. As a result, any company that desires to use CRISPR to develop human therapies may need to license not only The Broad’s patents on eukaryotic cells but also those the University of California expects to receive on all kinds of cells. The University of California patent would be on any use while The Broad’s patent would be for use only in eukaryotes.

Science Marches On!

CRISPR-Cas9 is unlikely to be the last genome-editing technology to ever be discovered and the appeal to the Federal Circuit is unlikely to inhibit the development of these leading edge technologies in any way. [12] For example, in 2015, Zhang and his colleagues discovered a version called Cpf1 which has now been patented and licensed to Editas Medicine of Cambridge – a leading gene editing company focused on the development curative therapeutics using the CRISPR/Cas9 technology. It appears likely then that the development of new technologies for genome-editing are inevitable. After all, bacteria have certainly come up with other ways to reach the same end, ways that are not covered by the patent claims made by either the University of California or The Broad. That could make either of these patents ultimately of little importance – especially if the licensing conditions provide researchers with incentives to come up with “invent-arounds”. Only one thing is certain – while the wheels of justice turn slowly, science inevitably marches on!
[1] The partners also include Intellia Therapeutics, Caribou Biosciences, Inc., ERS Genomics.

[2] The Broad Institute, et al v. The Regents of the University of California, TTAB Decision, February 15, 2017, Patent Interference No. 106-048 (DK).

[3] Hsu, Patrick D; Scott, David A; Weinstein, Joshua A; Ran F Ann; Konermann, Silvana; Agarwala, Vineeta; Li, Yinqing; Fine, Eli J; Wu, Xuebing; Shalem, Ophir; Cradick, Thomas J; Marraffini, Luciano A; Bao, Gang; Zhang, Feng (July 21, 2013). “DNA targeting specificity of RNA-guided Cas9 nucleases”, Nature Biotechnology, 31 (9); 827-832.

[4] A patent can only be awarded to the first inventor under 35 U.S.C. § 102(g). Interference proceedings are governed by 35 U.S.C. §135. When multiple parties contest the right to a patent, the Board of Patent Appeals and Interferences conducts an interference proceeding to determine the rights of the parties. An interference determines whether claims are patentable under 35 U.S.C. § 102(g), wherein “[a] person shall be entitled to a patent unless . . . during the course of an interference . . . . another inventor involved therein establishes . . . that before such person’s invention thereof the invention was made by such other inventor. . . .” Thus, if two parties claim patentably indistinct subject matter, a patent can be awarded to only the first inventor under 35 U.S.C. § 102(g). Courts use a two-way-test to determine if there is an interference-in-fact: “An interference exists if the subject matter of a claim of one party would, if prior art, have anticipated or rendered obvious the subject matter of a claim of the opposing party and vice versa.” 37 C.F.R. § 41.203 (2004). To prevail on its no interference argument, The Broad was required to show that neither of these conditions were met.

[5] To determine obviousness, “the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved.” Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17 (1966).

[6] “The consistent criterion for determination of obviousness is whether the prior art would have suggested to one of ordinary skill in the art that this process should be carried out and would have a reasonable likelihood of success, viewed in the light of the prior art.” (emphasis supplied) In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir. 22 1988).

[7] The Broad Institute, et al v. The Regents of the University of California, TTAB Decision, February 15, 2017, Patent Interference No. 106-048 (DK), at 23.

[8], Id., at 14.

[9] Id., at 15.

[10] Id at 19.

[11] Id., at 49.

[12] It is worth noting that the impact of patent-paper pairs on the dissemination of scientific innovation has been studied. See, Murray and Stern, Intellectual Property Rights and the Evolution of Scientific Journals as Knowledge Platforms, MIT Sloan School of Management Research Paper No. 5981-16, ,January 17, 2012; see also, Beaudry and Naserbacht, Impact of Patent Paper Pairs on the Quality of Biotechnology and Nanotechnology Patents In Quebec, DRUID15, Rome, June 15-17, 2015.


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